The pathological formation of clot known as thrombus


Thrombosis describes the pathological formation of a clot known as a thrombus consisting of platelets, fibrin, red cells and white cells, which may cause occlusion within blood vessels of the heart(1).

Endothelial cells maintain a nonthrombogenic lining in blood vessels. This results from several phenomena, including

The maintenance of a transmural negative electrical charge, which is important in preventing adhesion of circulating platelets

The release of plasminogen activators, which activate the fibrinolytic pathway

The activation of protein C, which degrades coagulation factors, a process involving thrombin and its endothelial cofactor (thrombomodulin)

The production of heparinlike proteoglycans, which inhibit coagulation

The release of prostacyclin (PGI2), a potent inhibitor of platelet aggregation. (2)

However the nonthrombogenic state of the blood vessels can be disrupted through a myriad of factors which can be broadly categorized into:

Trauma to the endothelial cells arising either from sheer stress or hypertension (4)

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Hypercoagulability of the blood which can be caused by a number of conditions such as hyperviscosity, deficiency of antithrombin III, nephrotic syndrome, changes after severe trauma or burn, disseminated cancer, late pregnancy and delivery, race, age, whether the patient is a smoker, and obesity. (5)

Disturbed blood flow which includes venous stasis which may occur in heart failure or after long periods of sedentary behavior. Atrial fibrillation, causes stagnant blood in the left can lead to a thromboembolism. Cancers or malignancies such as leukemia may cause increased risk of thrombosis by e.g. external compression on a blood vessel or (more rarely) extension into the vasculature (for example, renal cell cancers extending into the renal veins).(6)

Thrombosis can result in arterial occlusion and venous occlusion which can cause myocardial infarction, stroke and deep venous thrombosis , pulmonary embolism respectively. Thrombosis can also result in an embolus travelling to other parts of the body. (1)

Anticoagulant drugs such as heparin and warfarin, inhibit the development and enlargement of clots by actions on the coagulation phase. They do not lyse clots or affect the fibrinolytic pathways.


Warfarin is an oral vitamin K antagonist which is most useful in the management of pulmonary embolism and deep vein thrombosis. Vitamin K is required to catalyze the conversion of the precursors of vitamin K-dependent clotting factors II, VII, IX, and X.This involves the post translational gamma carboxylation of glutamic acid residues at the N-terminal end of the proteins. The gamma carboxylation step is linked to a cycle of enzyme reactions involving the active hydroquinone form of vitamin K (K1H2). The regeneration of K1H1 by an epoxide reductase is blocked by warfarin which then results in the the cessation of the coagulation cascade. (1)(2).

By stopping the coagulation cascade, Warfarin induces a state of hypocoagubility and thus prevents the clot or embolus from forming or increasing in size if already present(2)


Warfarin takes about 48-72 hours for an effect because of the time needed for the degradation of the clotting factors that have already been formed, if an immediate effect is required, heparin or a low molecular weight heparin can be administered.


The main indication for an oral anticoagulant is deep-vein thrombosis.

Patients with pulmonary embolism should also be treated, as should those with atrial fibrillation who are at risk of embolisation.


Whenever possible, the base-line prothrombin time should be determined but the initial dose should not be delayed whilst awaiting the result.

For patients who require rapid anticoagulation the usual adult induction dose of warfarin is 10 mg on the first day; subsequent doses depend upon the prothrombin time, reported as INR (international normalised ratio). For patients who do not require rapid anticoagulation, a lower loading dose can be used over 3-4 weeks. The daily maintenance dose of warfarin is usually 3-9 mg (taken at the same time each day). The following indications and target INRs take into account recommendations of the British Society for Haematology (8)


It is essential that the INR be determined daily or on alternate days in early days of treatment, then at longer intervals (depending on response) then up to every 12 weeks.(7)


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The main adverse effect of warfarin is haemorrhage. Checking the INR and omitting doses when appropriate is essential; if the anticoagulant is stopped but not reversed, the INR should be measured 2-3 days later to ensure that it is falling.(7)

Oral anticoagulants are teratogenic and should not be given in the first trimester of pregnancy. Women of child-bearing age should be warned of this danger since stopping warfarin before the sixth week of gestation may largely avoid the risk of fetal abnormality.


Apart from haemorrhage other side effects of warfarin are diarrhoea, unexplained drop in haematocrit, rash and jaundice.(7)

Since anticoagulant drugs like Warfarin prevent the formation of clots, the actual degradation of already existing clots belongs to another class of drugs known as fibrinolytics. They cause the lysis of already formed clots in both arteries and veins and reestablish tissue perfusion. (7)

This results in an improvement in vital sign readings such as heart rate, breathing rate and oxygen saturation.

Arterial thrombosis is associated with cerebral infarction (stroke) and transient ischaemic attacks. When transient ischaemic attacks occur, prophylaxis is required. In cerebral infarction anticoagulant treatment such as heparin and warfarin may increase risk of conversion of infarction of brain substance to haemorrhage. In this case the use of antiplatelet drugs such aspirin that inhibit thrombus formation on the arterial side is indicated. (7)


Aspirin is an antiplatet drug that blocks synthesis of thromboxane A2 from arachidonic acid in platelets by acetylating and hence inhibiting enzyme cyclo-oxygenase. Aspirin also prevents the production of prostacyclin from endothelial cells thereby inhibiting platelet aggregation. (7)


A single dose of aspirin 300 mg is given as soon as possible after an ischaemic event, preferably dispersed in water or chewed. The initial dose is followed by long-term treatment of aspirin 75 mg daily in order to prevent further cardiovascular disease events.If the patient is at a high risk of gastro-intestinal bleeding, a proton pump inhibitor can be added. (7)


Aspirin should be used with caution in asthma, uncontrolled hypertension, previous peptic ulceration, renal impairment, hepatic impairment and pregnancy. (7)


Aspirin use is contraindicated in patients with active peptic ulcers, haemophilia and aspirin-sensitive patients. (7)


In conclusion, whiles warfarin plays a major role in the management of venous thrombosis, aspirin plays a similarly major role in the management of arterial thrombosis. Together, these two drugs are major players in managing thrombosis.